Effects of phytoestrogen genistein on cytogenetic biomarkers in postmenopausal women: 1 year randomized, placebo-controlled study.

To evaluate in a twelve-month, randomized placebo-controlled study whether pure administration of phytoestrogen genistein (54 mg/day) might reduce cytogenetic biomarkers in peripheral lymphocytes of postmenopausal women. A total of 57 postmenopausal women met the criteria and were randomly assigned to receive phytoestrogen genistein (n = 30) or placebo (n = 27). There was no significant difference in age, length of time since menopause or body mass index between the two groups. After one year, plasma genistein level was 0.14 +/- 0.01 micromol/L in the control group and 0.72 +/- 0.08 micromol/L in the genistein group (P < 0.0001). At baseline, sister chromatid exchange rate was 4.97 +/- 2.17 in the control group and 4.96 +/- 1.83 in the genistein group (P = 0.89). After one year, sister chromatid exchange rate was 4.96 +/- 2.16 in the control group and 3.98 +/- 1.14 in the genistein group (P < 0.05). High frequency cells count was 3% in the genistein group and 5% in the control group (P < 0.05) at the end of the study. Chromosomal aberration frequency was 5.55% in the control group at time 0 and 5.75% in the genistein group; after one year, the figures were 5.86% in the control group and 4.5% in the genistein group (P < 0.05). After one year, there was a negative relationship between sister chromatid exchange rate and plasma levels (r = - 0.43; P < 0.05) in the genistein group. Phytoestrogen genistein has been shown in postmenopausal women to be effective in the reduction of cytogenetic biomarkers. The protective effect on genomic damage appears to be a particularly promising tool in reducing the risk of cancer.

Oxidative stress, sister chromatid exchanges and apoptosis in the pathogenesis of lymphocytopenia in ESRD patients.

BACKGROUND: In end-stage renal disease (ESRD) patients on hemodialysis (HD) there may be a link between oxidative stress, genomic damage and the tendency of peripheral lymphocytes to die by apoptosis. Our aim was to verify this hypothesis, and to ascertain whether the link, if present, could explain lymphopenia in uremic patients. METHODS: The series investigated comprised 55 participants: 30 HD patients on regular maintenance acetate-free bio-filtration (AFB) and 25 age-matched healthy volunteers. One blood sample was drawn from the cubital vein of each participant. In HD patients, samples were drawn 3 times: predialytic, postdialytic and interdialytic (24 hours after the end of the session). Thiobarbituric acid reactants (TBARs), sister chromatid exchange (SCE) rate, high frequency cells (HFCs), total circulating lymphocytes and the percentage of circulating apoptotic lymphocytes were assayed in all samples. A statistical analysis of the findings was made using multiple and linear regression. RESULTS: In AFB patients, TBAR levels appeared higher than in controls, even at baseline (2.15 +/- 0.5 micromol/L vs. 1.20 +/- 0.4 micromol/L; p < 0.05). The highest peak occurred at the end of the session (3.2 +/- 0.4 micromol/L; p < 0.05 vs. basal), and a prompt return to basal values was observed 24 hours later (2.2 +/- 0.6 micromol/L, p < 0.5 vs. basal). In AFB patients, the per-centages of HFCs (8.63% vs. 3%; p < 0.05), SCE (6 +/- 0.6 vs. 4.65 +/- 2.18; p < 0.04) and apoptotic lymphocytes (3-fold) were greater than in controls, even at baseline, whereas the values for total lymphocytes were lower (1,140 +/- 652 vs. 1,590 +/- 822). After an AFB session the differences between patients and control values appeared greater (HFCs, 16.81%, p < 0.04 vs. basal; SCE, 7.02 +/- 1.2, p < 0.03; apoptotic lymphocytes 3.5-fold greater than control values). Twenty-four hours later, a further increase was observed in the expression of genomic damage (HFCs, 50%, p < 0.05 vs. basal; SCE, 9.82 +/- 2.1, p < 0.03) and the percentage of apoptotic lymphocytes (4.7-fold greater than control values), while the lowest peak occurred for total circulating lymphocyte count (997 +/- 854, p < 0.04). At linear regression, a strong positive correlation was found between HFCs and TBARs at the beginning and at the end of the AFB session(r = 0.7, p < 0.03). With multiple regression analysis, a strong positive correlation was found between TBAR levels at the end of AFB session, HFC rate and apoptotic lymphocytes at 24 hours, with the last as the dependent variable (multiple r = 0.8, TBARs, beta = 0.51, p < 0.04; HFCs, beta = 0.43, p < 0.03). DISCUSSION AND CONCLUSIONS: An AFB session has an immediate impact, causing an increase in TBAR levels, genomic da-mage and lymphocytic apoptosis. Twenty-four hours after the session there was a further expression of genomic damage, and an increase in apoptosis, while the peak for lymphocytes dropped sharply. Our findings indicate that lymphopenia affecting end-stage renal disease (ESRD) patients may be strictly related to genomic damage exerted, at least in part, by TBARs, and to a dysregulation in programmed cell death.

Chromosomal damage and atherosclerosis. A protective effect from simvastatin.

In uremic patients, the frequency of sister chromatid exchanges appears markedly higher than in the general population. Statins are well known for their pleiotropic effects, which are independent of any reduction in cholesterol circulating levels. The aim of the present study was to determine the effects of exposure to escalating doses of simvastatin on the sister chromatid exchange rate in cultured lymphocytes in order to identify the influence of statin on genomic damage. Peripheral lymphocytic samples for culture were obtained from 25 healthy volunteers, 20 patients with documented carotid atherosclerosis and 30 atherosclerotic patients on maintenance regular acetate-free biofiltration. Hemodialyzed patients had a greater percentage of high frequency cells (50%) than healthy controls (3%) and a significantly higher average number of sister chromatid (9.82+/-2.1 vs. 4.65+/-2.18). The subgroup of hemodialyzed patients with high plaque score values was characterized by significantly greater values for both sister chromatid exchanges rate and high frequency cells percentage. Our findings demonstrate that there is an association between sister chromatid exchanges and high frequency cells rate and atherosclerosis in acetate-free biofiltration patients. In cultures with added simvastatin, high frequency cells percentages and mean sister chromatid exchanges levels were significantly lower than in cultures with an added vehicle alone, the reduction occurring in a dose-dependent fashion, above all in cultures from end stage renal disease patients. The findings, moreover, demonstrate new effects of simvastatin, which appeared to mitigate the expression of genomic damage in our model. However, it is not yet clear whether this effect is due to the prevention of genomic damage or to the potentiation of the DNA repair capacity. Statins may therefore have an anti-atherogenic action partly ascribable to their ability to provide protection against the development of atherosclerotic plaque.